17beta-tetrahydrofuranyloxy androstanes



United States Patent This invention relates to threne derivatives and to there-of.

The invention relates to novel 17/3-tetrahydrofuranyloxy steroids of the androstane series of the formula novel cyclopentanophenanprocesses for the preparation wherein R represents hydrogen, a lower alkyl group, such as methyl, ethyl, propyl and the like, a lower alkenyl group, such as vinyl and the like, or a lower alkynyl group, including halo-lower alkynyl wherein the halogen has an atomic number less than 53, such as ethynyl, fluoroethynyl, chloroethynyl, bromoethynyl, propynyl, trifiuoropropynyl, butynyl, hexynyl and the like and X represents the A, B, and C rings of the androstane molecule.

Included among the novel 17B-tetrahydrofuranyloxy steroids of the present invention are those represented by the following formulas:

ofi i/Q I 0 W m or,

3,341,527 Patented Sept. 12, 1967 In the above formulas R has the same meaning as previously set forth; Z represents a double bond or saturated linkage between C-1 and C-2; Z represents a double bond or saturated linkage between 0-4 and C-5; R represents hydrogen or methyl and when Z is a double bond, R is methyl R represents the oxygen or nitrogen linkage, i.e., O or The novel 17 3-tetrahydrofuranyloxy androstane derivatives of the present invention can also contain other conventional substituents, such as free hydroxyl groups, functionally converted hydroxyl groups, such as ester and ether groups, free keto groups, functionally converted keto groups, such as enol ether and ketal groups, lower alkyl groups, such as methyl, ethyl and propyl, lower alkylidene groups, such as methylene, ethylidene and propylidene, halogen atoms, such as fluorine, chlorine and bromine, amino groups, double bonds, and the like, which, depending on the particular substituent, can be present at one or more of positions 1 through l6, l8 and 19 on the steroid nucleus.

The novel l7/3-tetrahydrofuranyloxy steroids of the present invention exhibit enhanced anabolic activity when administered orally. These novel l7fltetrahydrofuranyloxy steroids also possess anti-estrogenic and anti-ovulatory activity, lower blood cholesterol levels, and inhibit the secretion of gonadotrophin by the pituitary gland.

The novel 17fi-tetrahydrofuranyloxy steroids of the present invention are prepared by reacting corresponding 17fi-hydroxy steroids, under substantially anhydrous conditions, with an excess of dihydrofuran prepared as described in US. Patent No. 2,556,325 to G. L. A. Fluchaire and G. Collardeau, e.g., from about 1 to about 2 or more molecular equivalents, for each hydroxyl group in the steroid starting material, in the presence of a small amount of an acidic catalyst, e.g., hydrochloric acid, ptoluenesulfonic acid, boron trifluoride etherate, and the like, either alone or together with an inert organic solvent such as benzene, diethyl ether or the like, at a temperature ranging from about 0 C. to about C., and preferably at room temperature (about 25 C.), for from about 5 minutes to about 48 hours.

The novel l7 8-tetrahydrofuranyloxy steroids of the present invention can be administered in any of a number of conventional pharmaceutical forms, and particularly in ones suited for oral administration, e.g., in solid form, such as in pills, powders, capsules, tablets, or the like, or in 3 liquid form, as syrups, emulsions, suspensions, and the like.

In order that those skilled in the art can more fully understand the present invention, the following examples are set forth. These examples are given solely for the purpose of illustrating the invention, and should not be considered as expressing limitations unless so set forth in the appended claims.

PREPARATION A A solution of 8.5 grams of l-chloro-Z-fiuoroethylene in 50 cc. of anhydrous diethyl ether was added dropwise over a half hour period, with stirring, to 15 cc. of a 1.4N solution of methyl lithium in anhydrous diethyl ether, contained under an inert nitrogen atmosphere, and this mixture was then held at room temperature, with stirring, for an additional 90 minutes. Next, a solution of 0.5 gram of A -androsten-3fi-o1-l7-one in 20 cc. of anhydrous diethyl ether was added dropwise, with stirring, over a 15 minute period, following which the resulting reaction mixture was poured into water and extracted with diethyl ether. The combined ether extracts were then washed with water, dried over anhydrous sodium sulfate and concentrated under vacuum. Chromatography of the resulting residue on basic alumina, using petroleum ether/ diethyl ether (8:2, respectively, by volume), as the eluant, followed by crystallization from acid-free methanol, gave 17u-fluoroethynyl-A -androstene-3[3,17,8-diol.

By repeating this procedure using 1,2-dichloroethylene and 1,2-dibromoethylene, respectively, in place of 1-chloro-2-fluoroethylene, 17a-chlor0ethynyl-A -androstene-3 8,l7fi-diol and 17a-bromoethynyl-A -androstene-3,8,17B-diol were obtained.

Similarly, by replacing A -androsten-3p,-ol-17-one with 19-nor-A -androsten-3fi-ol-17-one and using in turn each of the three 1,2-dihaloethylenes mentioned above,

17a-chloroethynyl-19-nor-A -androstene-3 [3, 17,8-diol and 17a-bromoethynyl-19-nor-A -androstene-3;3,17B-diol,

respectively, were obtained.

PREPARATION B A solution of 1 gram of ethylmagnesium bromide in 50 cc. of tetrahydrofuran was admixed with a solution of 6 grams of trifluoromethyl acetylene in 200 cc. of anhydrous diethyl ether, and the resulting mixture was allowed to stand at room temperature, with stirring, for 18 hours. Next, a solution of 1 gram of A -androsten-3,8- ol-l7-one in 50 cc. of anhydrous tetrahydrofuran was added, and the resulting reaction mixture was allowed to stand at room temperature, with stirring, for an additional 18 hours. Following this reaction period the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and then extracted with diethyl ether. The thus-obtained extract was washed with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the resulting residue from acetone/diethyl ether gave 17 a-trifluoropropynyl-A -androstene-3 ,8, 17 fi-diol.

By repeating this procedure using l9-nor-A -androsten-3B-ol-17-one as the steroid starting material, 17 a trifluoropropynyl-l9-nor-A -androsten-3B,17,8-diol was obtained.

PREPARATION C A solution of 1 gram of l7a-fluoroethynyl-A -androstene3B,17B-diol in a mixture of 80 cc. of toluene and 20 cc. of cyclohexanone was dried by distilling off 10 cc. of the solvent mixture. Next, a solution of 1 gram of aluminum isopropoxide in 7 cc. of anhydrous toluene was added, and the resulting reaction mixture was refluxed for 30 minutes. Following this reaction period 4 cc. of

acetic acid were added and the solvents were then removed by steam distillation. The product was then extracted several times with ethyl acetate and the organic extract was washed with an aqueous 5% hydrochloric acid solution, then with water, then with an aqueous 10% sodium carbonate solution and finally with water until neutral. The thus-obtained neutral solution was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the resulting residue from acetone/ hexane gave 17a-fluoroethynyl-A -androsten-17fi-ol-3-one.

This procedure was then repeated in every detail but one, namely,

17a-chloroethynyl-A -androstene-3 t3, l7fi-diol, l7a-bromoethynyl-A -androstene-3,8,17,6-diol and 17a-trifiuoropropyny1-A -androstene-3{3,17,8-diol were used as the steroid starting materials. In each case, the corresponding A -3-one, namely,

l7a-chloroethynyl-M-androsten- 17 {3-ol-3-one; 17a-bromoethynyl-A -androsten-17,8-01-3-one and 17a-trifiuoropropynyl-M-androsten-1713-01-3 -one,

respectively, were obtained.

PREPARATION D A solution of 1 gram of 17a-fluoroethynyl-l9-nor A -androstene-3B,17fl-diol in 20 cc. of pyridine was admixed with 1 gram of chromium trioxide in 20 cc. of pyridine, and the resulting reaction mixture was allowed to stand at room temperature overnight. Following this reaction period the reaction mixture was diluted with ethyl acetate, then filtered through Celite. The filtrate was then thoroughly washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone/hexane gave 17OL-fil1OI'O- ethynyl-A -androsten-l7B-ol-3-one.

By repeating this procedure using 17a-chloroethynyl-19-nor-A -androstene-3p,l7p-diol;

17a-bromoethynyl-1 9-nor-A -androstene-3 [3, l7fl-diol and 17 u-trifiuoropropynyl- 19-nor-A 1androstene-3 ,8, 1713- diol as the steroid starting materials,

l7a-chloroethynyl- 19-nor-A -androsten- 17 fl-ol-3-one;

17a-bromoethynyl-l9-nor-A -androsten-l7fl-ol-3-one and l7u-trifluoropropynyl-19-nor-A -androsten-17 6-01-3- one,

respectively, were obtained.

PREPARATION E A solution of 0.7 gram of 17u-fluoroethynyl-l9-nor- A -androsten-17fi-ol-3-one in 50 cc. of methanol was admixed with 0.1 cc. of concentrated hydrochloric acid, and the resulting reaction mixture was allowed to stand at room temperature overnight. Following this reaction period the reaction mixture was diluted with water and extracted with methylene dichloride. The thus-obtained extract was then washed with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the resulting residue from acetone/hexane gave 17a-fluoroethynyl-19-nor-A -androsten-17/8-ol-3-one.

By repeating this procedure using the remaining l9-nor- A -17 8-ol-3-ones obtained as described in Preparation D hereinabove as the steroid starting materials,

l7a-chloroethynyl-l9-nor-A -androsten-l7/8-ol-3-one; l7a-bromoethynyl-l9-nor-A -androsten-l7fi-ol-3-one and 17a-trifluoropropynyl-19-nor-A -androsten-17fl-ol-3one,

respectively, were obtained.

PREPARATION F 17a-methyl-A -androsten-17/3-ol-3-one,

17 nt-vinyl-M-androsten-17fi-ol-3-one, 17a-ethynyl-A -androsten-17B-ol-3-one, 17oz-fiuoroethynyl-Mandrosten-17fi-ol-3-one, 17a-chloroethynyl-A -androsten-17fi-ol-3-one, 17ot-bromoethynyl-A -androsten-17fi-ol-3-one, and 17a-trifluoropropynyl-A -androsten- 175-01-3 -one,

respectively, as the steroid starting materials, the corresponding l-dehydro steroids, namely,

17rx-methylA androstadien, l7a-vinyl-A f-androstadien-17B-ol-3-one, 17a-ethynyl-A androstadien-l 7fi-ol-3-one, 1704-11uoroethynyl-A f-androstadien-17B-ol-3-one, 17a-chloroethynyl-A f-androstadien-17fi-ol-3-one, 17ot-bromoethynyl-A flandrostadien-l7p ol-3-one, and 17wtrifluoropropynyl'A f-androstadienl7fi-ol-3-one,

respectively, were obtained.

Example I To a solution of 1 gram of testosterone in 25 cc. of benzene there was added 4 cc. of dihydrofuran. Next, approximately 5 cc. of the mixture of benzene and dihydrofuran was distilled 01f to remove moisture, and the remaining mixture was then cooled to room temperature. To the cooled mixture there was then added 0.1 gram of anhydrous p-toluenesulfonic acid, and the resulting reaction mixture was held at room temperature for 12 hours. Following this reaction period the reaction mixture was washed with an aqueous 5% sodium carbonate solution and then with water until neutral, then dried over anhydrous sodium sulfate and evaporated to dryness. The dry residue was then chromatographed by passing it dissolved in hexane, through a column of neutral alumina, thus giving 170: tetrahydrofuranyloxy M-androsten 3- one (the 17-tetrahydrofuranyl ether of testosterone).

This procedure was then repeated in way detail but one, namely, testosterone was replaced by 17u-methy1-A -androsten-17p-ol-3-one, 17a-vinyl-A -androsten-17/3-ol-3-one, 17u-ethynyl-A -androsten-17fi-ol-3-one, 17m-fluoroethynyl-A androsten-17/3-o1-3-one, 17a-chloroethynyl-A -androsten-17fl-ol-3-one, 17a-bromoethynyl-A -androsten-1 7,8-01-3 -one, 17a-trifluoropropynyl-A -androstem17p-ol-3-one, 19-nor-A -androsten-17,6-ol-3-one, l7rat-methyl-19-n0r-A -androsten-17p-ol-3-one, 17u-vinyl-19-nor-A -androsten-176-01-3-one, 17a-ethynyl-19-nor-A -androsten-173-01-3-0ne, 17a-fiuoroethynyl-19-nor-A -androsten-17,9-ol-3-one, 17 a-chloroethynyl-19-nor-A -androsten-17B-ol-3-one, 17a-bromoethynyl-19-nor-A -androsten-17,9-ol-3-one, 17a-trifluoropropynyl-19-nor-A -androsten-17/3ol-3-one, A -androstadien-17 fi-ol-3-one, 17a-methyl-A -androstadien-l7,8-ol-3-one,

17 a-vinyl-A -androst-adien-17 fi-ol-3-one, 17a-ethynyl-A -androstadien-17B-ol-3-one, 17a-fluoroethynyl-A -androstadien-17,8-ol-3-one,

17 e-chloroethynyl-A -androstadien-17,8-ol-3-one, 17 a-bromoethyny1-A -androstadien-17fi-ol-3-one, 17a-trifiuoropropyny1-A -androstadien-17,6-ol-3-one, 2ot-methylandrostan-17,6-ol-3-one, 2a-methyl-19-nor-androstan-17/3-ol-3-one, 2-methyl-A -androsten-17 p-o1-3-one, Z-methyl-19-nor-A -andr osten-17,B-ol-3-0ne, 2-oxaandr-osta-n-17/3-0l-3-one, 19-nor-2-oxaandrostan-17;8-o1-3-one, A -2-oxaandrosten-17/3-ol-3-one, 19-n0r-A -2-oxaandrosten-17,6-0L3-one, 17,e-hydroxy-A -androstene-[3,2c] -pyrazole, 17/3-hydroxy-19-nor-A -androstene- [3 ,2c] -pyrazole, 17,6-hydroxy-A -androsten- [3,2c] -oxazo1e, 17B-hydroxy-19-nor-A -androsten-[3,2c]--oxazole, 17fi-hydroxyandrostan- [2,3d]-isoxazole, 17 3-hydroxy-19-nor-androstan- [2,3 d] -isoxazole,

respectively. In each case the corresponding 17-tetrahydrofuranyl ether, namely,

17a-methy1-17,6-tetrahydrofuranyloxy-A -androsten- 3-one, 17a-vinyl-17/3-tetrahydrofuranyloxy-A -androsten-3-one, 17ot-ethynyl-17/i-tetrahydrofurany1oxy-A -androsten- 3-one, 17m-fluoroethynyl-17B-tetrahydrofuranyloXy-A androsten-3-one, 17ot-chloroethynyl-17p-tetrahydroturanyloxy-A androsten-3-one, 17u-bromoethynyl-17fl-tetrahydrofuranyloxy-n andr-osten-B-one, 17a-trifiuoropropynyl-17fi-tetrahydrofuranyloxy-A androsten-3-one, 17/3-tetrahydrofuranyloxy-19-nor-A -androsten-3-one, 17 a-methyl-17fl-tetrahydroturanyloxy-19-nor-A androsten-3-one, 17a-vinyl-17B-tetrahydrofuranyI0xy-19-nor-A androsten-Z-one, 17a-ethynyl-17B-tetrahydrofuranyloxy-19-nor-A androsten-3-one, 17a-fluoroethynyl-17/3-tetrahydrofuranyloxy-19-nor-A androsten-B-one, 17 u-chloroethynyl-17p-tetrahydrofuranyloxy-19-nor-A androsten-3-one, 17 ot-bromoethynyl-17 fi-tetrahydrofuranyloxy-19-nor-A adrosten-3-one, 17a-trifiuoropropyny1-17;8-tetrahydrofuran.yloxy-19-nor- A -androsten-3-one, 17,6-tetrahydrofuranyloxy-A -androstadien-3-one, 17a-methyl-17fi-tetrahydrofuranyloxy-A -androstadien- 3-one, 17m-vinyl-17fi-tetrahydrofuranyloxy-A -androstadien- 3 -one, 17u-ethynyl-17p-tetrahydrofuranyloxy-A -androstadien- 3-one, Y 17a-fluoroethynyl-17 8-tetrahydrofuranyloxy-A androstadien-3-one, 17a-chloroethynyl-17p-tetrahydrofuranyloxy-A androstadien-3-one, 17u-bromoethynyl-17;6-tetrahydrofuranyloxy-A androstadien-B-one, 17u-trifluoropropyny1-17B-tetrahydrofuranyloxy-A androstadien-I'a-one, 2a-rnethyl-17p-tetrahydrofuranyloxyandrostan-3-one, Zoe-methyl-17fl-tetrahydrofuranyloxy-19-nor-androstan-3- one, Z-methyl-17/3-tetrahydrofuranyloxy-A -androsten-3 -one, Z-methyl- 1 7/3-tetrahy drofuranyloxy- 19-nor-A -androsten- 3-one, 17 fi-tetrahydrofuranyloxy-Z-oxaandrostan-3-one, 17 B-tetrahydrofuranyloxy-19-nor-2-oxaandrostan-S-one, 17fl-tetrahydrofu-IanyIQXy-A -Z-oxaandrostan-3 -one, 17fl-tetrahydrofuranyloxy-19-nor-A -2-oxaandrostan- 3-one, 17 8-tetra-hydrofuranyloxy-n' -androstene-[3,2c]-pyrazo1e,

175-tetrahydrofuranyloxy-19-nor-A -androstene- [3,20]

pyrazole,

175-tetrahydro furanyl oxy-A -androsten- [3 ,2c] -oxaz ole,

17fi-tetrahydrofuranyloxy-19-nor-A -androsten- [3 ,2c]

oxazole,

l7B-tetrahydrofuranyloxyandrostan- [2,3 d] -isoxazole,

17 ,B-tetrahydrofuranyloxy-19-nor-androstan- [2,3 d]

isoxazole,

17fi-tetrahydrofuranyloxy-A -androsten-2,3 d-isOxazole,

and

17 fi-tetrahydrofuranyloxy- 19-nor-A androsten-2,3 d-

isoxazole, respectively, were obtained.

Example II The procedure of Example I was again repeated in every detail except for the following. 20 mg. of anhydrous p-toluenesulfonic acid were employed rather than 0.1 gram, the reaction was carried out for 15 minutes at room temperature, and

l9-nor-A -androsten-17B-ol-3-one, 17u-methy1-19-nor-A -androsten-l7(3-o1-3-one, 17a-vinyl-l9-nor-A -androsten-17fl-ol-3one, 17a-ethynyl-19-nor-A -androsten-175-01-3-one, 17 a-fluoroethynyl-l9-A -androsten- 1713-01-3 -one, 17a-ohloroethynyl-l9-nor-A -androsten-17/3-o1-3-one, 17a-bromoethynyl-19-nor-A -androsten-17/3-ol-3- one, and l7u-trifluoropropynyl-l9-nor-A -androsten-175-01-3- one, respectively, were used as the steroids starting materials. In each case, the corresponding l7-tetrahydrofurany1 ether, namely, 17fl-tetrahydrfuranyloxy-19-nor-A -androsten-3-one, Not-methyl-l7fl-tetrahydrofuranyloxyl-19-nor-A androsten-3-one, 17a-vinyl-17,8-tetrahydrofuranyloxy-19-nor-A androsten-3-one, 17a-ethynyl-17p-tetrahydrofuranyloxy-19-nor-A androsten-S-one, 17u-flu0roethynyl-1hit-tetrahydrofuranyloxy-l9-nor-A androsten-3-one, 17a-chloroethynyl-17fl-tetrahydrofuranyloxy-19-nor- A -androsten-3-one, 17a-bromoethynyl-17,8-tetrahydrofurfanyloxy-19-nor- A -androsten-3-one, and 17a-trifluoropropynyl-17fl-tetrahydrofuranyloxy-19-nor- A -androsten-3-one,

respectively, was obtained.

It will be obvious to those skilled in the art that other changes and variations can be made in carrying out the present invention without departing from the spirit and scope thereof as defined in the appended claims.

I claim:

1. A compound of the formula:

wherein Z is selected from the group consisting of a saturated linkage and a double bond; R is selected from the group consisting of hydrogen and methyl, and when Z represents a double bond, R is methyl.

2. 2m-rnethyl-17,8-tetrahydrofuranyloXyandrostan-3-one.

3. 2or-methyl-17B-tetrahydrofuranyloxy 19 nor-an drostan-3-one.

4. 2 methyl-l7,8-tetrahydrofuranyloxy-A -androsten- 3-one.

5. 2 methy1-l7B-te-trahydrofuranyloxy-19-nor-A -androsten-3-one.

6. A compound of the formula:

. T of mil wherein Z is selected from the group consisting of a saturated linkage and a double bond and R is selected from the group consisting of hydrogen and methyl.

17. 17,6 tetrahydrofuranyloxy 2 oxoandrostan 3- one.

18. tetrahydrofuranyloxy A 2 oxoandrosten- 3-one.

19. A compound of the formula 22. A compound of the formula wherein Z is selected from the group consisting of a satu- Wherein 1 is selected from the group consisting of hydro rated linkage aud a double bond and R is selected from gen and methyl and R is selected from the group conthe group Conslstmg of hydrogen and methylsisting of and 0123. 17B tetrahydrofuranyloxyandrostan 2,3d isoxa- 24. 17,8 tetrahydrofuranyloxy A androsten 2,3d- 20 isoxazole. .N

No references cited.

20. 17/3 tetrahydrofuranyloxy A androsten 3,2c- LEWIS GOTTS, Primary Examiner pyrazole.

21. 17B tetrahydrofuranyloxy A androsten 3,2c- 25 ELBERT ROBERTS Examiner oxazole. HENRY A. FRENCH, Assistant Examiner.

UPHTED STATES PATENT OFFHHE CERTIFICATE OF CORRECTION Patent No. 3,341,527 September 12, 1967 Alexander D. Cross It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 7, lines 56 to 65, the formula should 3 shown below instead of as in the patent: ppear as column 8, lines 5 to 15, the formula should appear as shown below instead of as in the patent:

Signed and sealed this 12th day of November 1968.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND OF THE FORMULA: 